Abstract
Alternative splicing can expand the diversity of proteomes. Homologous mutually exclusive exons (MXEs) originate from the same ancestral exon and result in polypeptides with similar structural properties but altered sequence. Why would some genes switch homologous exons and what are their biological impact? Here, we analyse the extent of sequence, structural and functional variability in MXEs and report the first large scale, structure-based analysis of the biological impact of MXE events from different genomes. MXE-specific residues tend to map to single domains, are highly enriched in surface exposed residues and cluster at or near protein functional sites. Thus, MXE events are likely to maintain the protein fold, but alter specificity and selectivity of protein function. This comprehensive resource of MXE events and their annotations is available at: http://gene3d.biochem.ucl.ac.uk/mxemod/. These findings highlight how small, but significant changes at critical positions on a protein surface are exploited in evolution to alter function.
Highlights
Alternative splicing (AS) refers to the assembly and rearrangement of different exons of a gene during pre-mRNA splicing such that different mRNAs and proteins are produced from the same gene
We compare proteins generated from mutually exclusive exon switching from 5 organisms
We found small regions that are different between the proteins and occur near important residue sites that determine the functions of the proteins
Summary
Alternative splicing (AS) refers to the assembly and rearrangement of different exons of a gene during pre-mRNA splicing such that different mRNAs and proteins are produced from the same gene. Amongst the most important exon-switching events are those that generate homologous mutually exclusive exons (MXEs), such that only one out of the two exons is retained while the other one is always spliced out This type of exon switching is less likely to be disruptive to highly organised globular protein structure [14,15] compared to AS events such as cassette exon removal. Consistent with this notion, homologous MXEs have been found to be highly enriched in proteomics experiments [16] and to be more conserved between species [17] compared to alternative transcripts generated by AS in general. MXEs have been shown to be enriched with muscle and membrane functions (such as transporter, signal transduction) [18,19]
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